This proposal focuses on research in the area of acyclic diastereoselective synthesis, with emphasis on the development of novel allylmetal reagents for application to the total synthesis of stereochemically complex natural products. It is expected that this methodology will facilitate synthesis of analogs and SAR studies of biologically active natural products, and other drug-like small molecules. Specific goals are: (I) Development of New Methodology Involving Allylboron Reagents. The double allylboration reaction is a powerful method for the stereocontrolled synthesis of 1,5-diol systems from aldehyde precursors, and has particular promise and utility in fragment assembly of complex synthetic intermediates in synthetic problems. Further development of this methodology is proposed. The discovery in the previous grant period that the Soderquist borane, TDDB-H (I- 13), effects hydroboration of allenes to give the kinetically stable (Z)-g-borylallylborane I-8b provides the foundation for generation of a range of new reagents that will significantly broaden the scope and utility of the double allylboration (and related double allylmetalation) process. The full scope of allylstannation reactions of allylstannanes 33 and I-22 be explored. This chemistry will provide solutions to fragment assembly processes that cannot be achieved by using first- generation double allylboration reactions. Building off the highly enantioselective hydroborations of allenes (and especially the enantioconvergent hydroboration reactions of racemic allenes) discovered in the previous grant period, the development of additional double allylmetalating reagents involving the enantioselective hydroborations of racemic allenylsilane I-23, allenylboronate I-28, and the kinetic resolution of I-34 will be pursued. The enantioselective hydroboration of achiral allenes such as I-38 and I-40 will also be studied. The greatest utility of the enantioselective allene hydroboration chemistry lies in the ability to generate bifunctional allylborane products that can be used for several C-C bond formation reactions, especially in the context of convergent fragment assembly. (II) Total Syntheses of Nigricanoside A. Nigricanoside is a potent, antimitotic glycolipids isolated from the green alga Avrainvillea nigricans, but the relative and absolute stereochemical of nigricanoside A has not been defined. Palmerolide A is a new enamide- containing polyketide that has remarkable selectivity against melanoma cell lines, with a selectivity index of e103 for the most sensitive cells. The nigricanosides and palmerolide A have structurally related 1,2,5-trialkoxypentene units that will be synthesized in a stereochemically general manner by using the chiral reagent III-3 deriving from hydroboration of racemic allene III-2. Subsequent manipulations of the allylboration product, III-4, will permit any stereoisomer (either enantiomer or diastereomer) of the 1,2,5-trialkoxypentene units of these natural products to be assembled in a concise, stereodivergent manner. This technology will be used to generate NMR database libraries (III-22 and III-23) which will permit the full stereochemistry of nigricanoside A to be assigned. This technology will also lead to concise, stereochemically controlled syntheses of nigricanoside A and selected analogs (stereoisomers). (III) Completion of Projects From the Preceding Grant Period. Total syntheses of peloruside A and amphidinol 3 that were pursued in the preceding grant period will be completed. New methodology, falling under aim (I), will be used to complete these syntheses, which have already progressed to very late stages.